الفهرس 
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Abstract
Diabetes mellitus (DM) is a metabolic disorder characterized by an impairment of carbohydrate, fat, and protein metabolism caused by either lack of insulin secretion or decreased sensitivity of the tissues to insulin. The prevalence of diabetes is increasing rapidly, and the disease incidence in 2010 was about 285 million people worldwide, and is projected to increase to 438 million in 2030. T2DM is an endocrine metabolic disorder characterized by increased insulin resistance in glucose-sensitive tissues and dyslipidemia. This leads to hyperglycemia, prolonged inflammation, and oxidative stress. Diabetic cardiomyopathy is a major complication that significantly contributes to morbidity and mortality in diabetics with few therapies. Moreover, antidiabetic drugs reported inconsistent or even adverse cardiovascular effects, suggesting that it is important to find novel therapeutic targets against diabetic cardiomyopathy. Melatonin (MLT) is a hormone with multifunctional antioxidant activity. It has attracted pronounced attention as a potential agent for the prevention and treatment of various diseases including diabetes. Therefore, the current study was designed to investigate the effect of MLT on hyperglycemia that influences the redox state, inflammation and apoptosis in the heart and pancreas of T2DM-induced rats at the early phase of the development of T2DM. Adult male Wistar rats, eight weeks old weighing (170-200) g, were used. After the acclimatization period, rats were randomly divided into four groups, 10 animals in each group as follows : 1- Control (Cont) group: Rats received only standard diet and tap water. 2- Melatonin (MLT) group: Rats were orally administered MLT (10 mg/kg.bw) by gavage daily for 15 days. 3- Diabetes (DM) group: Rats were injected with nicotinamide following STZ. 4- Diabetes + Melatonin (DM+MLT) group: Diabetic rats were orally administered MLT (10 mg/kg.bw) daily for 15 days using a gastric tube. Body weight and blood glucose were recorded along the experimental period in addition to the following parameters were estimated : 1- Biochemical analysis. A- serum glucose levels, serum insulin levels, HOMA-IR and HbA1c. B- Determination of serum lipid profile (TC, TG, HDL, LDL and VLDL). C- Determination of oxidative stress marker and antioxidants in heart and pancreas (4-HNE, GPx and GSH). D- Determination of serum (IL-1β, IL-6, IL-10 and TNF-α). E- Determination of heart function (CK-MB, LDH and cTnT). F- AST, ALT, Alb concentration, TB and TP levels. 2- Immunohistochemical analysis and quantification of P53, Bax, caspases-3 and Bcl-2. 3- Histological investigation of both heart and pancreatic tissues. 4- Cardiac fibrosis. All the data were statistically performed using GraphPad Prism 6.0 software. The results were expressed as the means ± standard error of the mean (SEM) for each variable were estimated. The results were summarized as follows: Treatment of diabetic rats with melatonin significantly normalized the levels of blood glucose, serum glucose, HbA1-c, and the lipid profile and improved the insulin level and insulin resistance compared with diabetic rats, affirming its antidiabetic effect. MLT significantly inhibited the development of oxidative stress and sustained the levels of glutathione and activity of glutathione peroxidase in the heart and pancreas of diabetic rats, indicating its antioxidant capacity. Additionally, MLT limited the increase in proinflammatory cytokines and enhanced the anti-inflammatory cytokine IL-10, indicating its anti-inflammatory effect. MLT controlled the levels of troponin T and creatine kinase-MB and lactate dehydrogenase activity, indicating that MLT can sustain the integrity of cardiomyocytes and ameliorate myocardial injury. MLT significantly ameliorated the elevation of AST, ALT and total bilirubin levels and the decrease in albumin and total protein levels in diabetic rats, reflecting the efficacy and safety application of melatonin. MLT upregulated bcl-2 expression and downregulated expression of pro-apoptotic proteins Bax, caspase-3 and p53, indicating that MLT can protect the heart and pancreas by modulating the apoptosis process during the early onset of T2DM. Histological examinations confirmed the ameliorative effects of MLT on T2DM-induced injury in the myocardium, pancreas and islets of Langerhans. Furthermore, MLT reduced fibrosis in the heart compared with the control, indicating its anti-fibrotic effect.